The last decade has witnessed tremendous advances in the understanding of, and the ability to manipulate, molecular and supramolecular assemblies (Moulton, B. et al., Chem. Rev., 2001, 101:1629-1658). There are new paradigms concerning the design and synthesis of a new generation of functional materials and molecules. Such advances are a consequence of the fundamental importance of intermolecular interactions, structure and cooperativity in many aspects of molecular science, from environmental science to molecular biology, to pharmacology, to materials science. Thus, the prospects for control and manipulation of materials at the molecular level, particularly in areas related to non-covalent bonding and nanotechnology, are now truly exceptional. However, whereas crystal structure determination has been a tool used by scientists since the 1920's, crystal structure prediction remains a largely unmet goal (Ball, P. Nature, 1996, 381:648-650; Gavezzotti, A. Acc. Chem. Res., 1994, 27:309-314). Furthermore, the existence of more than one crystalline form of a given molecular compound, typically in the form of polymorphs or solvates, represents both a problem and an opportunity (Desiraju, G. R. Science, 1997, 278:404-405; Bernstein, J. et al., Angew. Chem., Int. Ed. Engl., 1999, 38:3441-3461). This is particularly true for the pharmaceutical industry.
Crystal engineering (Schmidt, G. M. J. Pure Appl. Chem., 1971, 27:647-678; Desiraju, G. R. Crystal Engineering: the Design of Organic Solids, 1989, Elsevier: Amsterdam) is predicated on the assumption that crystals are de facto examples of self-assembly, i.e. crystals are comprised from a series of molecular recognition events or supramolecular synthons (Desiraju, G. R. Angew. Chem., Int. Ed. Engl., 1995, 34:2311-2327). It also offers a more realizable goal than crystal structure prediction since it relies on design and allows for careful selection of substrates, i.e. substrates that are predisposed to form predictable self-assembled superstructures can be targeted for study. Furthermore, the prototypal molecules used in crystal engineering contain exofunctional molecular recognition sites and they can be complementary with themselves (self-assembly) (Boucher, E. et al., J. Org. Chem., 1995, 60:1408-1412) or with other molecules (modular self-assembly) (Zaworotko, M. J. Chem. Soc. Rev., 1994, 23:283-288; Sharma, C. V. K. and M. J. Zaworotko Chem. Commun., 1996, 2655-2656). Coincidentally, most pharmaceutical molecules also contain exterior molecular recognition sites and, although this makes them susceptible to polymorphism and solvate formation, it also makes them attractive candidates for crystal engineering studies.
The ability of crystalline self-assemblies to be built from a bottom-up approach (Feynman, R. Engineering and Science, 1960, 22-36) could provide an exceptional control of the design of new phases at a molecular level. This contrasts with the current state-of-the-art: “The number of forms known for a given compound is proportional to the time and money spent in research on that compound” (McCrone, W. C. Polymorphism in Physics and Chemistry of the Organic Solid-State, pp. 726, Fox et al. Eds., Interscience: New York, 1965). This statement summarizes the predicaments and opportunities that one faces when dealing with a need to assert control over the composition and structure of pharmaceutical compounds in the solid state. Specifically, physical properties of crystalline solids are critically dependent on the internal arrangement of molecules or ions, making prediction of composition, crystal structure and morphology from knowledge of molecular structure a scientific challenge of the highest order. However, crystal structure prediction and even prediction of composition remains a largely unmet goal. Nonetheless, crystal engineering offers the intriguing possibility of using molecular components for their ability to impart functional characteristics (such as solubility, dissolution rate and stability) for the development of new delivery systems.
Undesirable physicochemical properties, physiological barriers, or issues of toxicity often limit the therapeutic benefit of drugs. This has motivated research in drug delivery systems for poorly soluble, poorly absorbed and labile substances. Crystalline self-assemblies represent a promising delivery modality for improving drug solubility, dissolution rate, stability and bioavailability. In addition, enhancement of drug activity can be achieved by means of inclusion complexation or molecular encapsulation. These systems offer various advantages over amorphous polymeric delivery systems both from design and stability perspectives. In this context, the existence of more than one crystalline form of a given compound, typically in the form of polymorphs or solvates, represents both a problem and an opportunity. Several factors further complicate the situation. For example, the Food and Drug Administration's (FDA's) strict purity requirements effectively mean that a particular crystalline phase of a drug must be selected and that its composition must be established. This has typically meant that a consistent X-ray powder diffraction (XPD) pattern is required (Federal Drug Administration Fed. Regist., 1997, 62:62893-62894). The need to ensure that processing produces both purity and ease of processing is problematic because many drug molecules are prone to form multiple phases, and crystal size and morphology can vary for a given phase. The commercial and public image costs of not ensuring that processing is reliable and reproducible is at best very high, as demonstrated by the recent pull back and reformulation of NORVIR by ABBOTT LABORATORIES).
That XPD patterns have been relied on for quality control is convenient but is in many ways unfortunate since XPD is not as foolproof as single crystal X-ray crystallography (e.g. similar patterns can be obtained for different phases, composition is not unambiguously determined), and XPD does not determine crystal packing. Knowledge of crystal packing is important because it helps explain the solubility and composition of a particular phase and provides other valuable information. However, the materials properties of pharmaceuticals and the existence of polymorphs are generally investigated at the tail end of the drug development process.
Accordingly, it would be advantageous to provide novel crystalline phases having properties, such as melting point, solubility, dissolution rate, chemical stability, thermodynamic stability, and/or bioavailability, which are different from existing solid forms of the pharmaceutical compound upon which they are based.